rs389328

Positions:

• chr7-94410821-T-A
• chr7-94410821-T-C
• chr7-94410821-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000089.4(COL1A2):​c.1198-68T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.864 in 1,548,134 control chromosomes in the GnomAD database, including 579,230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60918 hom., cov: 30)
  • Exomes 𝑓: 0.86 (518312 hom.)
• Consequence: COL1A2 NM_000089.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0400

Genes affected

COL1A2 (HGNC:2198): (collagen type I alpha 2 chain) This gene encodes the pro-alpha2 chain of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIB, recessive Ehlers-Danlos syndrome Classical type, idiopathic osteoporosis, and atypical Marfan syndrome. Symptoms associated with mutations in this gene, however, tend to be less severe than mutations in the gene for the alpha1 chain of type I collagen (COL1A1) reflecting the different role of alpha2 chains in matrix integrity. Three transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-94410821-T-A is Benign according to our data. Variant chr7-94410821-T-A is described in ClinVar as [Benign]. Clinvar id is 674812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A2	NM_000089.4	c.1198-68T>A		intron_variant		ENST00000297268.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A2	ENST00000297268.11	c.1198-68T>A		intron_variant		1	NM_000089.4	P1

Frequencies

GnomAD3 genomes AF: 0.893 AC: 135727 AN: 152026 Hom.: 60863 Cov.: 30

Gnomad AFR AF: 0.963

Gnomad AMI AF: 0.914

Gnomad AMR AF: 0.882

Gnomad ASJ AF: 0.778

Gnomad EAS AF: 0.978

Gnomad SAS AF: 0.850

Gnomad FIN AF: 0.866

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.859

Gnomad OTH AF: 0.876

GnomAD4 exome AF: 0.861 AC: 1202093 AN: 1395990 Hom.: 518312 AF XY: 0.860 AC XY: 600674 AN XY: 698584

Gnomad4 AFR exome AF: 0.966

Gnomad4 AMR exome AF: 0.888

Gnomad4 ASJ exome AF: 0.780

Gnomad4 EAS exome AF: 0.987

Gnomad4 SAS exome AF: 0.836

Gnomad4 FIN exome AF: 0.865

Gnomad4 NFE exome AF: 0.856

Gnomad4 OTH exome AF: 0.860

GnomAD4 genome AF: 0.893 AC: 135842 AN: 152144 Hom.: 60918 Cov.: 30 AF XY: 0.891 AC XY: 66296 AN XY: 74376

Gnomad4 AFR AF: 0.963

Gnomad4 AMR AF: 0.882

Gnomad4 ASJ AF: 0.778

Gnomad4 EAS AF: 0.978

Gnomad4 SAS AF: 0.850

Gnomad4 FIN AF: 0.866

Gnomad4 NFE AF: 0.859

Gnomad4 OTH AF: 0.878

Alfa AF: 0.873 Hom.: 7272

Bravo AF: 0.898

Asia WGS AF: 0.917 AC: 3188 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.48
DANN	Benign	0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs389328; hg19: chr7-94040133;